Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide

ABSTRACT

The present invention relates to new compounds of general formula 
                         
having thrombin-inhibiting activity. Exemplary are:
     1-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide, and   1-Methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/631,645, which was filed on Jul. 31, 2003, now U.S. Pat. No.6,900,229, and which is an application claiming the benefit under 35 USC119(e) of U.S. Provisional Patent Application No. 60/405,239, whichfiled on Aug. 22, 2002.

DESCRIPTION OF THE INVENTION

The present invention relates to new compounds of general formula

the tautomers and the salts thereof, particularly the physiologicallyacceptable salts thereof with inorganic or organic acids or bases, whichhave valuable properties.

The compounds of general formula I are prodrugs of thethrombin-inhibiting compound1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide (II),

which is already known from WO 98/37075, U.S. Pat. No. 6,087,380, U.S.Pat. No. 6,414,008, U.S. Pat. No. 6,469,039, and U.S. Pat. No.6,710,055. PCT Application No. WO 98/37075 entered the national stage inthe United States on Feb. 18, 1998, and subsequently issued as U.S. Pat.Nos. 6,087,380, 6,414,008, 6,469,039, 6,710,055. The prodrugs accordingto the invention are particularly suitable for subcutaneousadministration as they are well tolerated after subcutaneous injection,and in particular do not produce any local intolerance at the injectionsite when administered subcutaneously.

Thus, the present application relates to the new compounds of the abovegeneral formula I, the tautomers and the salts thereof as well as thepreparation thereof, the pharmaceutical compositions containing thepharmacologically effective compounds and the use thereof.

In the above general formula I

-   a) R′ denotes a hydrogen atom and R denotes a methoxycarbonyl group    or-   b) R′ denotes a hydrogen atom or a C1–6-alkyl group and R denotes a    hydroxy group.

The alkyl groups which contain more than 2 carbon atoms mentioned in theabove definition also include the branched isomers thereof such as forexample the isopropyl, tert-butyl and isobutyl group.

Preferred compounds of general formula I are those wherein

-   a) R′ denotes a hydrogen atom and R denotes a methoxycarbonyl group    or-   b) R′ denotes a hydrogen atom or a C1–3-alkyl group and R denotes a    hydroxy group,    the tautomers and the salts thereof.

The compound1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide, the tautomers and thesalts thereof, particularly the physiologically acceptable saltsthereof, are particularly preferred.

Particularly preferred salts are the maleate, the hydrochloride and themethanesulphonate of the compound1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide.

Another particularly preferred compound is1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide, the tautomers and thesalts thereof, particularly the physiologically acceptable saltsthereof.

Particularly preferred salts are the maleate, the methanesulphonate andthe sodium salt of the compound1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide.

The new compounds may be prepared by methods known per se, for exampleby the following methods:

A. In Order to Prepare a Compound of General Formula I wherein R Denotesa Hydroxy Group:

Reacting a compound of general formula

optionally formed in the reaction mixture,

-   wherein-   R′ is as hereinbefore defined and-   Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy,    n-propoxy, isopropoxy or benzyloxy group or an alkylthio or    aralkylthio group such as the methylthio, ethylthio, n-propylthio or    benzylthio group,    with an amine of general formula    H2N—OH  (IV).

The reaction is expediently carried out in a solvent such as methanol,ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxaneat temperatures between 0 and 150° C., preferably at temperaturesbetween 20 and 120° C., with a compound of general formula III or with acorresponding acid addition salt such as ammonium carbonate, forexample.

Compounds of general formula III and the preparation thereof aredescribed for example in WO 98/37075, U.S. Pat. No. 6,087,380, U.S. Pat.No. 6,414,008, U.S. Pat. No. 6,469,039, and U.S. Pat. No. 6,710,055which have been incorporated herein by reference in their entireties dueto the fact that PCT Application No. WO 98/37075 entered the nationalstage in the United States on Feb. 18, 1998, and subsequently issued asU.S. Pat. Nos. 6,087,380, 6,414,008, 6,469,039, and 6,710,055.

B. In Order to Prepare a Compound of General Formula I wherein R′Denotes Hydrogen:

converting a compound of general formula

wherein

-   R is as hereinbefore defined and-   R″ denotes a group which can be converted into a carboxyl group by    hydrolysis, treatment with an acid or base, thermolysis or    hydrogenolysis,    into a compound of general formula I wherein R′ denotes hydrogen, by    hydrolysis, treatment with an acid or base, thermolysis or    hydrogenolysis.

Examples of a group which may be converted into a carboxy group includefor example a carboxyl group protected by a protecting group, such asthe functional derivatives thereof, e.g. the unsubstituted orsubstituted amides, esters, thioesters, trimethylsilylesters,orthoesters or iminoesters, which may conveniently be converted into acarboxyl group by hydrolysis,

-   the esters thereof with tertiary alcohols, e.g. the tert.-butyl    ester, which may conveniently be converted into a carboxyl group by    treatment with an acid or thermolysis, and-   the esters thereof with aralkanols, e.g. the benzyl ester, which may    conveniently be converted into a carboxyl group by hydrogenolysis.

The hydrolysis is conveniently carried out either in the presence of anacid such as hydrochloric acid, sulphuric acid, phosphoric acid, aceticacid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof orin the presence of a base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide in a suitable solvent such as water, water/methanol,water/ethanol, water/isopropanol, methanol, ethanol,water/tetrahydrofuran or water/dioxane at temperatures between −10 and120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture.

If R″ in a compound of formula V contains the tert.-butyl ortert.-butyloxycarbonyl group, for example, these may also be cleaved bytreatment with an acid such as trifluoroacetic acid, formic acid,p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoricacid or polyphosphoric acid, optionally in an inert solvent such asmethylene chloride, chloroform, benzene, toluene, diethyl ether,tetrahydrofuran or dioxane, preferably at temperatures between −10 and120° C., e.g. at temperatures between 0 and 60° C., or also thermally,optionally in an inert solvent such as methylene chloride, chloroform,benzene, toluene, tetrahydrofuran or dioxane and preferably in thepresence of a catalytic amount of acid such as p-toluenesulphonic acid,sulphuric acid, phosphoric acid or polyphosphoric acid, preferably atthe boiling temperature of the solvent used, e.g. at temperaturesbetween 40 and 120° C.

If R″ in a compound of formula V contains the benzyl orbenzyloxycarbonyl group, for example, these may also be cleaved byhydrogenolysis in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide, preferably at temperatures between 0 and 50° C., e.g.at ambient temperature, and a hydrogen pressure of 1 to 5 bar.

Compounds of general formula V and the preparation thereof aredescribed, for example, in WO 98/37075, U.S. Pat. No. 6,087,380, U.S.Pat. No. 6,414,008, U.S. Pat. No. 6,469,039, and U.S. Pat. No.6,710,055.

C. In Order to Prepare a Compound of General Formula I wherein R Denotesa Methoxycarbonyl Group:

reacting a compound of general formula

wherein

-   R′ is as hereinbefore defined, with a compound of general formula    Z2-COOCH3  (VII),-   wherein-   Z2 denotes a nucleofugic leaving group such as a halogen atom, e.g.    a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methanol,ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane,dimethylsulphoxide or dimethylformamide, optionally in the presence ofan inorganic or a tertiary organic base, preferably at temperaturesbetween 20° C. and the boiling temperature of the solvent used.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl ortetrahydropyranyl group,

-   a protecting group for a carboxyl group may be a trimethylsilyl,    methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and-   protecting groups for an amino, alkylamino or imino group may be an    acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,    tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or    2,4-dimethoxybenzyl group and additionally, for the amino group, a    phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or by ether splitting, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group ispreferably cleaved hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidizing agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesbetween 0 and 50° C., but preferably at ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

An allyloxycarbonyl group is cleaved by treatment with a catalyticamount of tetrakis-(triphenylphosphine)-palladium(0), preferably in asolvent such as tetrahydrofuran and preferably in the presence of anexcess of a base such as morpholine or 1,3-dimedone at temperaturesbetween 0 and 100° C., preferably at ambient temperature and under inertgas, or by treatment with a catalytic amount oftris-(triphenylphosphine)-rhodium(I)chloride in a solvent such asaqueous ethanol and optionally in the presence of a base such as1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C.

The compounds of general formulae III to VII used as starting materialswhich are known from the literature are obtained by methods known fromthe literature and also their preparation is described in WO 98/37075,U.S. Pat. No. 6,087,380, U.S. Pat. No. 6,414,008, U.S. Pat. No.6,469,039, and U.S. Pat. No. 6,710,055.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into theirphysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, methanesulphonicacid or maleic acid.

Moreover, if the new compounds of formula I thus obtained contain acarboxy group, they may subsequently, if desired, be converted into thesalts thereof with inorganic or organic bases, particularly forpharmaceutical use into the physiologically acceptable salts thereof.Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

As already mentioned hereinbefore, the new compounds of general formulaI and their salts as prodrugs of the active substance II have valuableproperties, as they are converted into thrombin-inhibiting activesubstance II after oral or parenteral administration. In particular,they are characterized by being well tolerated after subcutaneousadministration.

For example the compounds

-   A=1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide and-   B=1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide    were investigated for their degree of tolerance when administered by    subcutaneous route by comparison with active substance II:

Solutions of the test substances were each administered by subcutaneousroute once a day on three successive days to two female rabbits (age: 11to 14 weeks, weight: 2.0 to 3.5 kg). At the same time as the substanceswere administered a placebo solution was injected contralaterally intothe same animal. The animals were killed 48 hours after the lastadministration and dissected. The injection sites for administering thetest substances were compared histologically with the sites of theplacebo injections.

In contrast to compound II, which produced clear signs of inflammationat the injection sites, compounds A and B proved to be very welltolerated locally.

In order to investigate the conversion of the prodrugs A and B into theactive substance II, 1.0 ml of blood were taken from the centralauricular artery of each of the test animals with K-EDTA syringes atvarious times after subcutaneous administration. The blood wascentrifuged and the plasma was acidified with the same volume of 0.2 Mhydrochloric acid. These solutions were stored at −20° C. Theconcentrations of the active substance II were measured using anHPLC-MS/MS apparatus (Perkin Elmer Sciex API 300 LC-MS/MS system). Thedetection limit was 4 ng/ml. In this way it was established that aftersubcutaneous injection the prodrugs A and B were converted into theactive substance II in the test animals.

In view of their pharmacological properties the new compounds and thephysiologically acceptable salts thereof are suitable for the preventionand treatment of venous and arterial thrombotic diseases, such as forexample the treatment of deep leg vein thrombosis, for preventingreocclusions after bypass operations or angioplasty (PT(C)A), andocclusion in peripheral arterial diseases such as pulmonary embolism,disseminated intravascular coagulation, for preventing coronarythrombosis, stroke and the occlusion of shunts or stents. In addition,the compounds according to the invention are suitable for antithromboticsupport in thrombolytic treatment, such as for example with rt-PA orstreptokinase, for preventing long-term restenosis after PT(C)A, forpreventing metastasis and the growth of clot-dependent tumors andfibrin-dependent inflammatory processes such as arthritis, for example.

The dosage required to achieve such an effect is appropriately 0.03 to10.0 mg/kg, preferably 0.05 to 3.0 mg/kg by subcutaneous route, 0.1 to3.0 mg/kg, preferably 0.3 to 1.0 mg/kg by intravenous route, and 0.1 to50.0 mg/kg, preferably 0.3 to 10.0 mg/kg, by oral route, in each caseadministered 1 to 4 times a day. For this purpose, the compounds offormula I prepared according to the invention may be formulated,optionally together with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,water/propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose orfatty substances such as hard fat or suitable mixtures thereof, toproduce conventional galenic preparations such as plain or coatedtablets, capsules, powders, suspensions, suppositories or injectablesolutions. They are preferably incorporated in diluents such as, forexample, water, water/ethanol, water/glycerol, water/sorbitol,water/polyethyleneglycol or water/propyleneglycol in order to prepare aninjectable solution.

The Examples that follow are intended to illustrate the invention inmore detail:

EXAMPLE 11-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide

A solution of 0.71 g (17.0 mmol) of lithium hydroxide-hydrate in 175 mlof water was added to a suspension of 8.50 g (15.24 mmol) of1-methyl-2-[4-(N-methoxycarbonyl-amidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide (for preparation see WO98/37075, U.S. Pat. No. 6,087,380, U.S. Pat. No. 6,414,008, U.S. Pat.No. 6,469,039, and U.S. Pat. No. 6,710,055) in 140 ml oftetrahydrofuran, with stirring, at ambient temperature. The clearsolution thus obtained was stirred for a further two hours at ambienttemperature, then approx. one third of the volume was evaporated offusing the rotary evaporator, the remaining solution was diluted withapprox. 200 ml of water and adjusted to pH 5 to 6 with hydrochloricacid. The precipitated solid was suction filtered, dissolved in amixture of methanol and dichloromethane (1:1), undissolved ingredientswere filtered off and the filtrate was evaporated to dryness. Theproduct thus obtained was triturated with acetone, suction filtered,washed with acetone and diethyl ether and dried.

Yield: 80.5% of theory. C27H27N7O5 (529.56) Mass Spectrum: (M+H)⁺=530(M−H)⁻=528 (M+Na)⁺=552 ¹H-NMR (d6-DMSO): δ=2.61 (t, 2H); 3.58 (s, 3H);3.77 (s,3H); 4.19 (t, 2H); 4.60 (d, 2H); 6.76 (d, 2H); 6.96 (m, 2H);7.09 to 7.10 (m, 2H); 7.40 (d, 1H); 7.47 (s, 1H); 7.56 (t, 1H); 7.80 (d,2H); 8.38 (m, 1H); 8.50 to 9.20 (broad d, 2H) ppm; carboxyl-H notvisible.

EXAMPLE 21-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide-methanesulphonate

A solution of 181 mg (1.89 mmol) of methanesulphonic acid in 5 ml ofmethanol was added to a suspension of 1.00 g (1.89 mmol) of1-methyl-2-[4-(N-methoxycarbonyl-amidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amidine in 35 ml of methanolwith stirring at ambient temperature, forming a clear solution. Afterone hour the solution was filtered, the filtrate was evaporated down toapprox. 10 ml and then acetone was added dropwise until slightcloudiness set in. After another hour's stirring at ambient temperaturethe product precipitated was suction filtered, washed with acetone anddiethyl ether and dried.

Yield: 84.7% of theory. C27H27N7O5×CH4O3S (625.67) Mass Spectrum:(M+H)⁺=530 (M+CH3SO3⁻)⁻=624 Melting point: from 214° C. decomposition

EXAMPLE 31-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide-maleate

Prepared analogously to Example 2 from1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide and maleic acid.

Yield: 69.2% of theory. C27H27N7O5×C4H4O4 (645.63) Mass Spectrum:(M+H)⁺=530 (M−H)⁻=528 (M+C4H3O4⁻)⁻=644 Melting point: 179–180° C.

EXAMPLE 41-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide-sodium salt

A solution of 90.6 mg (2.27 mmol) of sodium hydroxide in 1.0 ml of waterwas added to a suspension of 1.20 g (2.27 mmol) of1-methyl-2-[4-(N-methoxycarbonyl-amidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide in 30 ml of ethanolwith stirring at ambient temperature. A clear solution formed, fromwhich the product was precipitated by slow dropwise addition of diethylether. After filtering, the product was washed with approx. 20 mldiethyl ether and dried at 60° C.

Yield: 72.3% of theory Melting point: amorphous C27H26N7O5Na×H2O(569.54) Elemental Analysis:

calculated: C 56.94 H 4.96 N 17.78 found: C 56.68 H 5.17 N 17.55

¹H-NMR (d6-DMSO): δ=2.20 (t, 2H); 3.59 (s, 3H); 3.76 (s, 3H); 4.10 (t,2H); 4.60 (d, 2H); 6.77 (d, 2H); 7.00–7.13 (m, 3H); 7.17 (d, 1H); 7.38(d, 1H); 7.48 (s, 1H); 7.57 (t, 1H); 7.80 (d, 2H); 8.34 (m, 1H);8.60–9.22 (d, broad, 2H) ppm.

EXAMPLE 51-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide

20.0 g (41.45 mmol) of1-methyl-2-(4-cyano-phenylaminomethyl)-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide (for preparation see WO98/37075, U.S. Pat. No. 6,087,380, U.S. Pat. No. 6,414,008, U.S. Pat.No. 6,469,039, and U.S. Pat. No. 6,710,055) were added with stirring toa solution of HCl gas in ethanol (500 ml) saturated while cooling withice, then the cooling bath was removed and the mixture was stirred for afurther five hours. The reaction mixture was then evaporated down invacuo using the rotary evaporator, while the temperature was keptconstantly below 30° C. The residue was dissolved in 200 ml of ethanoland slowly 20.0 g (198 mmol) of triethylamine were added while coolingwith ice. Then 3.75 g (54.0 mmol) of hydroxylamine-hydrochloride wereadded and the mixture was stirred for two hours at ambient temperature.The product precipitated was suction filtered and re-crystallized fromethanol/dichloromethane (2:1).

Yield: 61.5% of theory Melting point: 162–164° C. C27H29N7O4 (515.58)Mass Spectrum: (M+H)⁺=516 (M+Na)⁺=538 ¹H-NMR (d6-DMSO): δ=1.12 (t, 3H);2.69 (t, 2H); 3.76 (s, 3H); 3.98 (q, 2H); 4.22 (t, 2H); 4.52 (d, 2H);5.55 (s, broad, 2H); 6.43 (t, 1H); 6.70 (d, 2H); 6.89 (d, 1H); 7.09 to7.20 (m, 2H); 7.40 (m, 3H); 7.48 (s, 1H); 7.55 (t, 1H); 8.40 (m, 1H);9.24 (s, 1H) ppm.

The following may be prepared analogously to Example 5:

-   1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-methoxycarbonylethyl)-amide,-   1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-n-propyloxycarbonylethyl)-amide,-   1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-isopropyloxycarbonylethyl)-amide,-   1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-n-butyloxycarbonylethyl)-amide,-   1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic    acid-(N-2-pyridyl-N-2-isobutyloxycarbonylethyl)-amide.

EXAMPLE 61-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide

Prepared analogously to Example 1 from1-methyl-2-[4-(N-hydroxyamidino)-phenyl-aminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide.

Yield: 66.2% of theory. C25H25N7O4 (487.58) Mass Spectrum: (M+H)⁺=488(M−H)⁻=486 (M+Na)⁺=510

EXAMPLE 71-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide-hydrochloride

A solution of HCl in ethanol was produced by stirring 152 mg (1.94 mmol)of acetylchloride into 5.0 ml of ethanol. The solution obtained wasadded at ambient temperature to a solution of 1.0 g (1.94 mmol) of1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide in 50 ml of absoluteethanol, then it was evaporated down to a volume of approx. 10 ml usinga rotary evaporator and then ethyl acetate was added dropwise withstirring until slight cloudiness could be observed. The mixture wasstirred for approx. a further 15 hours, then the product precipitatedwas suction filtered, washed with diethyl ether and dried.

Yield: 78.3% of theory. Melting point: 155–157° C. Mass Spectrum:(M+H)⁺=516 (M+Na)⁺=538 C27H29N7O4×HCl×H2O (570.05) Elemental Analysis:

calculated: C 56.89 H 5.66 N 17.20 Cl 6.22 found: C 56.80 H 5.67 N 17.06Cl 6.25

EXAMPLE 81-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide-maleate

1.0 g (1.94 mmol) of1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide was dissolved withheating in 100 ml of absolute ethanol and 225 mg (1.94 mmol) of maleicacid were added. The solution was then evaporated down to a volume ofabout 15 ml and ethyl acetate was added dropwise at ambient temperatureuntil slight cloudiness could be detected. After stirring overnight theprecipitated product was suction filtered, washed with diethyl ether anddried.

Yield: 61.0% of theory. Melting point: amorphous. C27H29N7O4×C4H4O4 MassSpectrum: (M+H)⁺=516 (M+Na)⁺=538

EXAMPLE 91-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide-methanesulphonate

Prepared analogously to Example 8 from1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide and methanesulphonicacid.

Yield: 67.4% of theory. Melting point: 128–130° C. Mass Spectrum:(M+H)⁺=516 (M+Na)⁺=538

EXAMPLE 10

Dry Ampoule Containing 75 mg of Active Substance Per 10 ml

Composition:

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0mlPreparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

EXAMPLE 11

Dry Ampoule Containing 35 mg of Active Substance Per 2 ml

Composition:

Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0mlPreparation:

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried.

To produce the solution ready for use, the product is dissolved in waterfor injections.

EXAMPLE 12

Tablet Containing 50 mg of Active Substance

Composition:

(1) Active substance  50.0 mg (2) Lactose  98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5) Magnesium stearate  2.0mg 215.0 mgPreparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side.

Diameter of the tablets: 9 mm.

EXAMPLE 13

Tablet Containing 350 mg of Active Substance

Composition:

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesium stearate  4.0mg 600.0 mg

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side.

Diameter of the tablets: 12 mm.

EXAMPLE 14

Capsules Containing 50 mg of Active Substance

Composition:

(1) Active substance  50.0 mg (2) Dried maize starch  58.0 mg (3)Powdered lactose  50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mgPreparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatin capsules in acapsule filling machine.

EXAMPLE 15

Capsules Containing 350 mg of Active Substance

Composition:

(1) Active substance 350.0 mg (2) Dried maize starch  46.0 mg (3)Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mgPreparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatin capsules in acapsule filling machine.

EXAMPLE 16

Suppositories Containing 100 mg of Active Substance

1 suppository contains:

Active substance  100.0 mg Polyethyleneglycol (M.W.1500)  600.0 mgPolyethyleneglycol (M.W.6000)  460.0 mg Polyethylenesorbitanmonostearate  840.0 mg 2000.0 mg

1. A pharmaceutical composition comprising: a compound of the formula

 wherein (i) R′ denotes a hydrogen atom and R denotes a methoxycarbonylgroup, or (ii) R′ denotes a hydrogen atom or a C₁₋₆-alkyl group and Rdenotes a hydroxy group, and wherein the alkyl groups which contain morethan 2 carbon atoms also include the branched isomers thereof, or atautomer or pharmaceutically acceptable salt thereof,  thepharmaceutical composition adapted for administration to a patient in anamount of approximately 0.03 mg to approximately 10.0 mg per kilogram ofpatient weight.
 2. The pharmaceutical composition according to claim 1,wherein a) R′ denotes a hydrogen atom and R denotes a methoxycarbonylgroup or b) R′ denotes a hydrogen atom or a C₁₋₃-alkyl group and Rdenotes a hydroxy group, while the C₃-alkyl group also includes anisopropyl group, or a tautomer or pharmaceutically acceptable saltthereof.
 3. The pharmaceutical composition according to claim 1, whereinthe compound comprises1-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide, or a tautomer orpharmaceutically acceptable salt thereof.
 4. The pharmaceuticalcomposition according to claim 1, wherein the compound comprises1-Methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide, or a tautomer orpharmaceutically acceptable salt thereof.
 5. The pharmaceuticalcomposition according to claim 1, wherein the compound comprises themaleate, the hydrochloride, or the methanesulphonate of1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide.
 6. The pharmaceuticalcomposition according to claim 1, wherein the compound comprises themaleate, the methanesulphonate, or the sodium salt of the compound1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide.
 7. The pharmaceuticalcomposition according to claim 1, further comprising one or more inertcarriers and/or diluents.
 8. The pharmaceutical composition according toclaim 1, packaged in an ampoule or capsule.
 9. The pharmaceuticalcomposition according to claim 1, formed as a tablet.
 10. A method fortreating thrombus formation comprising: administering an antithromboticamount of a pharmaceutical composition comprising: a compound of theformula

 wherein (i) R′ denotes a hydrogen atom and R denotes a methoxycarbonylgroup, or (ii) R′ denotes a hydrogen atom or a C₁₋₆-alkyl group and Rdenotes a hydroxy group, and wherein the alkyl groups which contain morethan 2 carbon atoms also include the branched isomers thereof, or atautomer or pharmaceutically acceptable salt thereof,  thepharmaceutical composition adapted for administration to a patient in anamount of approximately 0.03 mg to approximately 10.0 mg per kilogram ofpatient weight.
 11. The method according to claim 10, wherein a) R′denotes a hydrogen atom and R denotes a methoxycarbonyl group or b) R′denotes a hydrogen atom or a C₁₋₃-alkyl group and R denotes a hydroxygroup, while the C₃-alkyl group also includes an isopropyl group, or atautomer or pharmaceutically acceptable salt thereof.
 12. The methodaccording to claim 10, wherein the compound comprises1-Methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide, or a tautomer orpharmaceutically acceptable salt thereof.
 13. The method according toclaim 10, wherein the compound comprises1-Methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide, or a tautomer orpharmaceutically acceptable salt thereof.
 14. The method according toclaim 10, wherein the compound comprises the maleate, the hydrochloride,or the methanesulphonate of1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide.
 15. The methodaccording to claim 10, wherein the compound comprises the maleate, themethanesulphonate, or the sodium salt of the compound1-methyl-2-[4-(N-methoxycarbonylamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylicacid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide.
 16. The methodaccording to claim 10, wherein the pharmaceutical composition furthercomprising one or more inert carriers and/or diluents.
 17. The methodaccording to claim 10, wherein the pharmaceutical composition ispackaged in an ampoule or capsule.
 18. The method according to claim 10,wherein the pharmaceutical composition is formed as a tablet.